L-alpha-Acetylmethadol (LAAM) is an orally effective long-acting narcotic analgesic that has been proposed for use in maintenance treatment of persons physically dependent on narcotic agonists. The overall objective of the entire project is to obtain as much information as possible on the general cardiovascular effects of LAAM and congeners l-alpha-acetylnormethadol, norLAAM; l-alpha-acetyldinormethadol dinorLAAM). Previous data from this laboratory have shown that LAAM produces a marked negative chronotropic response in isolated right atria of guinea pigs and in the intact anesthetized dog. The drug has a biphasic inotropic effect: lower concentrations increase the contractile height of the guinea pig left atrium and higher concentrations decrease contractile height. Both major metabolites of LAAM also possess chronotropic and inotropic properties. There are three goals for the project during the next funding period. First, the effect of chronic LAAM administration on cardiac function of guinea pigs will be studied. We want to learn not only whether or not function is altered directly but also whether tolerance develops to the cardiac effects already observed in naive animals. The effect of chronic LAAM treatment on the ability of the heart to respond to known cardiac drugs also will be studied. Another goal of the coming year is to learn whether norLAAM and/or dinorLAAM produce cardiovascular effects in the anesthetized naive dog. And finally, we plan to study the relationship, if any, between changes in disposition and changes in cardiovascular responses to LAAM.